Chaotic neovascularization induced by aggressive fibrosarcoma cells overexpressing S-adenosylmethionine decarboxylase.

ABSTRACT

S-adenosylmethionine decarboxylase is a key enzyme in the biosynthesis of polyamines essential for cell proliferation. Overexpression of S-adenosylmethionine decarboxylase in rodent fibroblasts led to aggressive transformants (Amdc-s cells) that had unforeseen high invasive capacity in nude mice, invading rapidly from the subcutaneous injection site into the peritoneal cavity and its organs. In vitro, these cells were much more invasive than Ras-oncogene-transformed fibroblasts, or human HT-1080 fibrosarcoma and MDA-MB-231 breast cancer cells. In immunohistological characterization, Amdc-s-induced tumors showed chaotic neovascularization, with abundant pleomorphic vessel-like structures that had noncontiguous or totally missing laminin (basement membrane) and CD31 (endothelial cell) immunoreactivity. Gene expression and protein analyses of Amdc-s cells showed them to overexpress several pro-angiogenic molecules, including vascular endothelial growth factor (VEGF-A), and to exhibit profound down-regulation of the anti-angiogenic thrombospondin-1 (TSP-1). By reintroduction of TSP-1 into Amdc-s cells, the high invasiveness was efficiently inhibited in vitro. Interestingly, Amdc-s cells showed up-regulation of hepatocyte growth factor (HGF) and also expressed the MET receptor, creating thus an autocrine loop able to regulate VEGF-A and TSP-1 levels. Further, we found Amdc-s cells to express increased amounts of matrix metalloproteinase-2 (MMP-2) and the large isoform of tenascin-C (TN-C), which may also contribute to the angiogenic switch and invasiveness. Consequently, Amdc-s cells offer an excellent model to sort out the key molecules of aggressive tumor growth, and thereby help in designing rational, novel anti-vascular and other cancer therapies.